CN101282715A - Method of storing nanoparticle formulations - Google Patents
Method of storing nanoparticle formulations Download PDFInfo
- Publication number
- CN101282715A CN101282715A CNA2006800312295A CN200680031229A CN101282715A CN 101282715 A CN101282715 A CN 101282715A CN A2006800312295 A CNA2006800312295 A CN A2006800312295A CN 200680031229 A CN200680031229 A CN 200680031229A CN 101282715 A CN101282715 A CN 101282715A
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- China
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- active agent
- composition
- agent
- nutrient
- liposomal formulation
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- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 160
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- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 claims description 27
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- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 7
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- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1277—Preparation processes; Proliposomes
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
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Abstract
The present invention is a method for storing a liposome or nanoparticle formulation formed by the combination of at least one phospholipid, at least one sufactant and at least one hydrophilic polymer. The method incldes freezing such a formulation, and storing it for a period of at least three days.
Description
Background of invention
Invention field
The method of relate generally to storing nanoparticle of the present invention.More specifically, the present invention relates to store the method for the liposome of stability with raising and storage characteristics.
Background information
Several standard techniques have been used for the storage of liposome and nano-particle, as cold preservation, freezing/dry (or lyophilizing), and dehydration.In freeze drying process, can use preservation filler (antifreezing agent) to strengthen storage as sugar and sugar derivatives.These preserve that fillers help but the stability or the damage problem that always do not overcome liposome in freezing and the defreezing method fully.Aspect the economy of present method and the industrial efficiency limitation being arranged also, can cause shelf life limited under cold preservation or freezing conditions because mix this preservation filler.And, relevant with lyophilizing freezing, thaw and/or drying means or dewatering in, the harmful change to biology, chemistry and/or the physical property of the active agent of sealing can appear.Present freeze drying process (freezing and dry cycle) also may be very slow and consuming time.An important concern is that if lyophilizing is carried out too soon or carried out under unsteered temperature, then it may cause the change of biology, chemistry and/or the physical property of liposome membrane, thereby causes storing unstability.Finally, this also may influence the character of the active agent of sealing nocuously.
Use separately or with conventional freezing method that other method is used in combination in, for example since be exposed to the film formed highly compressed mechanical stress of liposome vesicle that ice crystal forms or freezing, thaw and/or dehydration in the expansion and the contraction of solute in the liposome, may cause damage.The expansion of liposome membrane can cause the weakness in the liposome membrane and the formation of fistula and crackle in the freeze cycle process, and the loss that this causes integrity and stability again causes leakage problem.In addition, one liposome is bunchy closely mutually usually, makes that in the refrigerating process of routine, the expansion of a liposome may cause pressure, causes the negative consequence to the adjacent liposomes integrity.
Usually, prior art has its limitation in the following areas: the shelf life of liposome, and storage, processing and embedding character, and keep (i) liposome or Nanoparticulate compositions; The (ii) ability of the integrity of active agent.In addition, many technology are owing to the size of the length of finishing the required time of technology and the processing batch of material that causes thus has extra limitation, and this has increased resulting cost.
Summary of the invention
The present invention is a kind of method that stores liposome or nanoparticle formulations, and this liposome or nanoparticle formulations form by making up at least a phospholipid, at least a surfactant and at least a hydrophilic polymer.This method comprises freezing this preparation and it is stored at least three days time.
The accompanying drawing summary
Fig. 1 show according to the present invention freezing and thaw after Liposomal formulation.
Invention is described
Embodiment of the present invention are discussed below. In describing embodiment, in order to know purpose, use concrete term. But, the invention is not restricted to the concrete term of so selecting. Although concrete exemplary embodiment has been discussed, should be understood that doing so only is for illustrative purposes. Those skilled in the relevant art will appreciate that, can use other component and structure, and without departing from the spirit and scope of the present invention. The list of references of all references is incorporated herein by reference each piece quilt is introduced separately as it.
As used herein, nano-particle can be defined as general spherical vesicles, and it has by amphiphile and promptly has skin or the film that the component of hydrophilic segment and hydrophobic part forms, and this skin or film are around kernel.Usually, the size of nano-particle is less than about 1000nm.What the present invention was concerned about especially is the nano-particle that can be used for or be used as drug delivery system.For example, be used for nano-particle of the present invention and can be used to seal the chemical compound that is delivered to biosystem, this chemical compound includes but not limited to: (i) bioactive compound such as medicine; Or (ii) abiotic reactive compound such as photographic developer.Liposome be exemplary types can be used for nano-particle of the present invention.Liposome is a vesicle, and it comprises the double-layer of lipoid around moisture nuclear, and it also can seal biological activity and abiotic reactive compound.The present invention strengthens and the integrity of protection nano-particle or liposome membrane, make its avoid various stress such as freezing, thaw and stir the damage that causes.Therefore, the present invention has improved stability, storage and/or the shelf life characteristics of nano-particle such as liposome.As used herein, freezing can being under any temperature is generally less than 0 ℃, and it provides solid-state, for example about-20 ℃ or following ,-78 ℃ or following (being dry-ice temperature) approximately, or-196 ℃ or following (being liquid nitrogen temperature) approximately.Although usually described the present invention having liposome aspect the embodiment of representative nano-particle, this is not restrictive, and the present invention also is applicable to other nano-particle.
The compositions of various liposomees and other nanoparticle formulations is well-known in the art, and in industrial medical science, cosmetics and other purpose of being used for.Liposomal formulation is the various lipids of different mol ratio and the combination that other composition includes but not limited to target part and bioactive substance.Method for preparing lipidosome generally is known.Liposome can be prepared into various sizes, and for example diameter greater than 500nm, and can be the single or multiple lift vesicle less than 20nm-.They can be used to seal the various materials that are used for medical science and non-medical purpose.Liposome can be used for embedding active agent such as pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod, abiology biologically active prod such as photographic developer, and composition thereof, and these reagent are transported to concrete position.But a subject matter of Liposomal formulation is its storage to be used to study or commercial object and the ability (being shelf life) that do not have degradation of lipid and/or active agent to discharge.Therefore, pass in time that liposome leaks and degraded aspect vesicle stability be subject matter.
Embodiment of the present invention relate to storing nanoparticle formulations such as Liposomal formulation, but go for the nano-particle that is made of amphiphile such as lipid of other type.Be applicable to that preparation of the present invention comprises the nano-particle with membrane component, it comprises at least a amphiphile, at least a surfactant and at least a hydrophilic polymer.Hydrophilic polymer can be unmodified; Combine modification by addition functional group with nano-particular film; Perhaps chemical bonding is to other component of amphiphile, surfactant or nano-particular film.Modification is so that the membrane-bound example of hydrophilic polymer and nano-particle can comprise that the functional group of addition polarity or formation electric charge is with the polar group stronger association of generation with film forming amphiphile or surfactant.Alternatively; hydrophilic polymer can covalent bonding to film forming amphiphile or surfactant; thereby it is present in the surface of nano-particle or liposome, and to protect and to keep its integrity, perhaps it can mix the inner lipid layer of liposome or nanoparticle formulations.Hydrophilic polymer can be bonded to amphiphile or surfactant by biodegradable or hydrolyzable key such as amide or ester bond or by more stable key such as amine or ehter bond.
Bound by theory does not believe that hydrophilic polymer integrity to liposome or nano-particular film in freezing, cold preservation, lyophilizing, dehydration and/or rehydration method provides protection.The integrity of protection nano-particle and liposome membrane has been preserved physics, chemistry and the biological property of nano-particle and Liposomal formulation, has also kept embedding in nano-particle or the liposome or the character of any chemical compound of sealing.Therefore, liposome or nanoparticle formulations preserved embedding be used for medical science, veterinary and non-medical use as but be not limited to biotechnology, electronics, defence and agrotechnical encapsulation object, and allow Liposomal formulation to store and transportation with freezing state.
The ratio of amphiphile and surfactant is variable, and it can be the ratio of any suitable nano-particle or liposome desired use.Recognize that amphiphile and surfactant all can have two affine surface-active properties; Yet when two kinds of components had similarity, for this description, amphiphile can be considered to main membrane component, and surfactant is an accessory constituent.Therefore, the ratio of amphiphile and surfactant is at least about 51: 49, can be greatly to 99: 1.In exemplary, the ratio of amphiphile and surfactant is at least about 70: 30, can be about 80: 20 or 90: 10.As known in the art, add the variation that surfactant can cause nano-particle or liposome physics or chemical property, with the character that realizes some expectation such as the reduction of phase transition temperature or membrane permeability.This variation of Nanoparticulate compositions within the scope of the present invention.
Hydrophilic polymer can be present in the film of nano-particle or liposome with various amounts, and this amount is about 25 mole percents of about 0.1-based on the total amount meter of amphiphile and surfactant.Be bonded in the embodiment of the phospholipid that forms liposome at hydrophilic polymer, contain the hydrophilic polymer of the 75-90 weight % that has an appointment and the lipid of 25-10 weight %, this is corresponding to the phospholipid of the hydrophilic polymer modification of about 33 mole percents of about 0.11-.As skilled in the art to understand, the amphiphile that the hydrophilic polymer of mole percent is changed into the modification of mole percent will depend on the molecular weight of unmodified amphiphile and the molecular weight of hydrophilic polymer.The calculating of ratio is that those skilled in the art are well-known.Embodiment of the present invention can comprise the hydrophilic polymer (modified amphiphile of about 27 mole percents of for example about 3-) of about 3-20 mole percent or the hydrophilic polymer (modified amphiphile of about 13 mole percents of for example about 3-) of 3-10 mole percent.Certain embodiments of the present invention are by the preparation of the modified amphiphile of about 5 mole percents of about 4-, thereby about 2.5-is provided the hydrophilic polymer of about 4.5 mole percents.The optimised quantity of hydrophilic polymer can easily be determined by routine experiment by those skilled in the art.
The compositions and methods of the invention are for being effectively by the nano-particle of various preparation of compositions and liposome, and described compositions includes but not limited to the combination of phospholipid, Semen sojae atricolor lipid, phosphoethanolamine, cholesterol, fat melting rhzomorph (lysolipids), surfactant and composition thereof and at least a hydrophilic polymer such as Polyethylene Glycol, polyaeryloyl morpholine, poly--the 2-ethyl-2-oxazoline, polyvinylpyrrolidone, methoxy poly (ethylene glycol) (mPEG) and derivant and mixture.The example of phospholipid of the present invention includes but not limited to phosphatidylcholine, phosphatidyl glycerol, phosphatidylinositols, PHOSPHATIDYL ETHANOLAMINE and sphingomyelin.Be used for LYSO-PHOSPHATIDYLCHOLINE LYSOPC that representative surfactants of the present invention can include but not limited to that double-stranded phospholipid, fat melting rhzomorph, bile acid, myristoyl surfactant, palmityl surfactant, stearoyl surfactant, glycerin mono-fatty acid ester, ceramide, PEG-ceramide, C 18-ether connects, polyethylene glycol-ethylene copolymer, block copolymer, fatty acid and composition thereof.The example that is used for fat melting rhzomorph of the present invention includes but not limited to single palmitoylphosphatidyl choline (MPPC), single lauroyl phosphatidylcholine (MLPC), single myristoyl phosphatidylcholine (MMPC), single stearoyl phosphatidylcholine (MSPC) and composition thereof.Be used for representative hydrophilic polymers of the present invention and include but not limited to Polyethylene Glycol, polyaeryloyl morpholine, poly--the 2-ethyl-2-oxazoline, polyvinylpyrrolidone, methoxy poly (ethylene glycol) (mPEG) and composition thereof.The example that is used for active agent of the present invention includes but not limited to pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod, abiology biologically active prod such as photographic developer, and composition thereof.The active agent of exemplary types comprises for example anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.Exemplary antineoplastic agent includes but not limited to anthracycline drug such as amycin (doxorubicin) and Epirubicin (epirubicin); Taxanes is as paclitaxel and taxotere; With platinum class medicine (plat ins) as cisplatin, carboplatin and oxaliplatin.
One embodiment of the invention are used and to be comprised phospholipid DPPC, fat melting rhzomorph MSPC and functionalised with the phospholipid that comprises hydrophilic polymer such as DSPE-mPEG-2000 and/or DSPE-mPEG-5000 as 1; the Liposomal formulation of 2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine (DSPE), wherein hydrophilic polymer is connected to lipid by amido link.Comprise the phospholipid that mol ratio was low to moderate 90: 10: 1: the fat melting rhzomorph: the liposome composition of the phospholipid of hydrophilic polymer functionalized is proved to be effective in freezing and storage method.Therefore, the present invention has broad-based application, and it can be used to industrial liposome product to increase efficient and reduce production costs.The present invention can be used for any nano-particle or Liposomal formulation with the integrity of protection liposome at freezing, cold preservation, dehydration and freeze-drying process.
In one embodiment, the present invention relates to a kind of storage and have the method for augmented performance as the nanoparticle formulations such as the Liposomal formulation of stability, storage, embedding or release characteristics.Find, hydrophilic polymer is mixed the film of nano-particle such as liposome, strengthened stability, storage, embedding and the release characteristics of this vesicle.Comprise in nano-particle and Liposomal formulation that hydrophilic polymer has limited freezing, cold preservation, thaws, lyophilizing, dehydration or other are used for that auxiliary described preparation stores, harmful change of biology, chemistry and the physical property of stability and caused nano-particle of handling of method or liposome membrane.Therefore, protect, keep and/or strengthened the integrity of original membrane with the existence of nano-particle or the bonded hydrophilic polymer of Liposomal formulation.
In the past, can not use freezing effectively separately in order to store liposome.Most of liposome products have alarm tag, write: " please don't be freezing ".Such example is found on the label of commercially available product such as Doxil, AmBisome, DepoCyt and several lipid of cosmetics.Being used for preparation of the present invention can provide a kind of compositions, and wherein liposome and nano-particle can be frozen, and the content that does not damage film integrality or seal.Therefore, use preparation of the present invention will allow single bottle and many bottles of combination products to be frozen and to store to be used to distribute purpose.That is, special benefits of the present invention is that Liposomal formulation can be frozen and transport with single container, and it can be a unit dosage form, rather than betransported with the container that separates, like that need preparation again before using at once.
The present invention also comprises the method for preparation and storing nanoparticle or Liposomal formulation, and this method comprises that the amphiphile or the lipid that will be fit to formation nano-particle or liposome composition mix with hydrophilic polymer, freezing and storage.This nano-particle and liposome can use the common known method in this area to form, for example by the amphiphilic component is mixed under suitable condition with aqueous solution.Suitable method is well-known to those skilled in the art.See for example U.S. Patent No. 6,200,598 and 6,726,925 of Needham; The U.S. Patent No. 5,094,854 of Ogawa, they are incorporated herein by reference.Nano-particle and liposome composition can store the short time in full minute or a few hours and longer time such as a couple of days, several weeks, several months or several years.
And described method allows nano-particle and Liposomal formulation to be distributed into unit dose with a plurality of or single bottle before or after freezing and storage.Nano-particle of the present invention and Liposomal formulation can be sealed at least a in the following material: cell toxicant and non-cytotoxicity medicine, gene prod or biological reagent, and abiology reagent such as photographic developer, it can use immediately or frozen-pack becomes test kit.
Another care in people and/or animal in the process of use nano-particle and liposome composition is that said composition can be discerned and remove as reticuloendothelial system (RES) by the defence of the health of nature, has limited their effective cycle time and therapeutic use.Checked several method, prepared " stealthy (stealth) " compositions as the size of optimization nano-particle and liposome composition or by in composition film, adding some composition removal biology process that they avoid nature with protection or " hiding ".In storage process, nano-particle and liposome tend to size to be increased, and causes the loss of film integrality and stability.As the replacement scheme of the independent composition of special adding this to produce " stealthy " characteristic, develop a kind of nano-particle and liposome size and inhomogeneity method of expecting of keeping, can help to increase and be kept among the experimenter effectively circulation time.Reason thus, the size of protection nano-particle or liposome in freezing, cold preservation, dehydration or freeze-drying process can be very important to their integrity and performance.Therefore, the preparation that improves nano-particle or liposome stability can keep particle size constant in storage process, has kept its treatment effectiveness.
In an exemplary, use known method, with hydrophilic polymer (or being modified) combination of amphiphile, surfactant and effective dose, form nano-particle to comprise the amphiphile of hydrophilic polymer.For example, amphiphile, surfactant and hydrophilic polymer (or being modified to comprise the amphiphile of hydrophilic polymer) combination in organic solvent can be removed and desolvates, add aqueous solution then.Active agent can be used known technology for example to utilize the pH gradient to be loaded into the inner space of nano-particle then.Can use known technology for example to extrude the screening nano-particle by suitable polycarbonate filter.Screening can be carried out before or after loading nano-particle with active agent.Final nanoparticle size can or be the about 500nm of about 10-, the about 500nm of about 25-, the about 200nm of about 50-or the about 125nm of about 80-less than about 1000nm.The effective dose of hydrophilic polymer can be determined by the following method: the preparation nano-particle, and freezing under desired temperatures, store the suitably long time, thaw said preparation and meter are shown the characteristic of the nano-particle of stability.The characteristic of measuring can be for example leakage of granular size or active agent.Then, the amount of hydrophilic polymer can change to realize the stability of expected degree in the initial preparation.
Behind the preparation nano-particle, preparation can be with solid-state in for example about-20 ℃ or following, freezing and storage under-78 ℃ of following or about-196 ℃ or following temperature approximately.In exemplary embodiment, nano-particle can store about three days or more days with freezing state, and does not have significant physical property to change when thawing.In other embodiments, nanoparticle formulations can store about seven days or more days, and about one month or longer, about three months or longer, or about 24 months, or even the longer time.Said preparation can save as tank solution, perhaps before freezing, can be divided into unit dose to be used for distribution.Except storing, refrigerated nanoparticle formulations can be transported to it with the site that is used.For example, preparation can prepare in production equipment, is divided into unit dose, and is freezing and be transported to it with the position that is used.This provides the advantage that is better than existing preparation and distribution method.Use traditional method, nanoparticle formulations often is divided into the component part in order to transport, so that prevent stability lost.For example, often with a plurality of bottle transportations, wherein liposome is in a container for Liposomal formulation, and the solution of active agent is in another container.Before use, two independent containers must be with the mode combination of guaranteeing that active agent loads before administration.The mistake for preparing in this final solution may cause lacking effectiveness.Utilize the present invention, removed this integrating step from.Therefore, using the site, preparation thaws, and can directly use or administration.This helps the use of compositions, and guarantees compositions correct preparation for effective administration.
Therefore, the invention provides the method for storage, transportation and administration nano-particle or Liposomal formulation.The preparation that stores and/or transport according to the present invention can be with any mode administration that is used for this special preparation.That medication comprises is oral, rectum, peritoneum, vein and cheek administration, but can use any desired route of administration according to active agent and avtive spot thereof.Said preparation can be individually dosed; Promptly, perhaps combine with other treatment reagent or excipient before use as prepared.Excipient can comprise other solid or liquid excipient such as aqueous solution, suspension, emulsion, solid excipient, dispersant etc.If nanoparticle formulations directly uses after preparation, promptly before storing and transporting, use, then finally use consistent with the purposes of nanoparticle formulations.
Will be further understood that these and other feature and advantage of the present invention by following representative embodiment, described representative embodiment is not intended to limit the scope of the invention.
Representative embodiment 1
With dipalmitoyl phosphatidyl choline (DPPC), 1-stearyl-2-LYSO-PHOSPHATIDYLCHOLINE LYSOPC (MSPC) and N-(carbonyl-methoxy poly (ethylene glycol)-2000)-1,2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine (DSPE-mPEG-2000) is dissolved in dichloromethane with mol ratio at 90: 10: 4.Remove organic solvent by rotary evaporation then.Mixture is used the hydration under pH4 of 300mM citrate buffer solution then, obtain the final lipid concentration of about 100mg/ml.The suspension that forms is extruded (Hope by two polycarbonate membrane filters then, M.J. etc., Production oflarge unilamellar vesicles by a rapid extrus ion procedure, characterization of size, trapped volume and ability to maintaina membrane potential.
Biochim.
Biophys.
Acta.812:55-65,1985).The initial particle mean size of the final Liposomal formulation among this embodiment is 98-122nm.(usually, the granularity of liposome of the present invention will be 50-500nm according to extrusion method.) by with liposome and sodium carbonate liquor and medicament mixed and the medicine amycin is loaded in the liposome.In brief, the 0.5mM sodium carbonate of the amycin solution (5.8mg/ml) of 1.6ml and 1.2ml is added in the liposome mixture of 1.9ml, in 35 ℃ of balances 60 minutes.Then with the liposome of drug loading and empty liposome in-20 ℃ of storages.The variation of monitoring granularity.The liposome composition that does not add mPEG by identical method preparation.Table 1 explanation, along with the adding of mPEG, liposome particle size keeps identical freezing with the back that thaws, and is recorded by the liposome and the stability test of standard, and liposome is stable to reach 24 months most.By contrast, lack the liposome of hydrophilic polymer mPEG in the freezing and back instability of thawing.This instable evidence is that granularity increases in freezing back.Fig. 1 has shown the Liposomal formulation after the freeze/thaw.Before and after freeze/thaw, the not significant difference of visual appearance and granularity.
Table 1 freezing and thaw after liposome particle size change
Representative embodiment 2
As described in representative embodiment 1, the another kind of Liposomal formulation that contains amycin of preparation.
With sample freezing 1 week, 1 month and 3 months under-20 ℃.At each time point, measure that amycin content, 1.2 μ m % recovery, % down seals, liposome concentration, pH and vesicle size.At initial time point (t=0), being with or without three samples of freezing test down, to determine freezing influence to Liposomal formulation.In addition, a sample is exposed to three freeze-thaw circulations, whether can be harmful to determine repeatedly the freeze-thaw circulation.
By following table as can be seen, when t=0, Liposomal formulation has similar characteristic under environment or freezing conditions.Even three freeze-thaw circulations do not influence film integrality yet.Preparation is still stable-20 ℃ of storage lifves through 3 months.In this time range, do not observe vesicle size, amycin content, seal or the significant change of lipid content.Although the outside pH of the sample that records has slight change at different time points, the pH measured value of observing the liposome for preparing in carbonate buffer solution is along with CO
2Gas is run out of from bottle and is changed in time.But as shown in table 2, the variation of pH does not influence membrane stability, because 3 months the pH data and the data class in when week are seemingly.
Table 2 multiple freezing and thaw after liposome stability
| T=0 is not freezing | T=0 is freezing | T=0 freeze/thaw 3 times | 1 week | 1 month | 3 months | |
| DOX (amycin) (mg/ml) | 1.85 | 1.76 | 1.77 | 1.83 | 1.76 | 1.73 |
| % reclaims, 1.2 μ m | 99.2 | 99.8 | 99.9 | 100.2 | 99.3 | 100.5 |
| % seals | 99.9 | 99.5 | 99.4 | 99.5 | 99.5 | 98.2 |
| TL (mg/ml) | 35.1 | 35.2 | 35.0 | 34.9 | 34.9 | 35.7 |
| pH | 8.15 | 7.85 | 7.85 | 8.50 | 8.84 | 8.52 |
| Size | 97.0 | 98.0 | 98.3 | 98.9 | 96.7 | 97.8 |
The embodiment that exemplifies in this description and discuss only is intended to instruct the known preparation of those skilled in the art inventor and uses best mode of the present invention.All should not think Anywhere in this description limits the scope of the invention.All embodiment that provide all are representational and indefinitenesses.As skilled in the art to understand, in view of above-mentioned instruction, without departing from the invention, the above-mentioned embodiment of the present invention can modify or change.Therefore, should be understood that the present invention can implement in the mode outside the specifically described mode in the scope of claims and their equivalent.
Claims (104)
1. the method for a storing nanoparticle formulations, this nanoparticle formulations has at least a amphiphile, at least a surfactant and at least a hydrophilic polymer, and this method comprises freezing described preparation and stores at least three days time.
2. the method for claim 1, it also comprises the described refrigerated Liposomal formulation of transportation and the described preparation that thaws in another position.
3. the process of claim 1 wherein that described nano-particle is a liposome.
4. the method for claim 3, wherein, described amphiphile comprises at least a phospholipid.
5. the method for claim 4, wherein:
A. described at least a phospholipid is selected from phosphatidylcholine, phosphatidyl glycerol, phosphatidylinositols, PHOSPHATIDYL ETHANOLAMINE, sphingomyelin and composition thereof;
B. described at least a surfactant is selected from LYSO-PHOSPHATIDYLCHOLINE LYSOPC that double-stranded phospholipid, fat melting rhzomorph, bile acid, myristoyl surfactant, palmityl surfactant, stearoyl surfactant, glycerin mono-fatty acid ester, ceramide, PEG-ceramide, C18-ether connects, polyethylene glycol-ethylene copolymer, block copolymer, fatty acid and composition thereof; With
C. described at least a hydrophilic polymer is selected from Polyethylene Glycol, polyaeryloyl morpholine, poly--the 2-ethyl-2-oxazoline, polyvinylpyrrolidone, methoxy poly (ethylene glycol) (mPEG) and composition thereof.
6. the method for claim 5, wherein, described hydrophilic polymer is by hydrolyzable key and phospholipids incorporate.
7. method that stores Liposomal formulation, this Liposomal formulation has at least a phospholipid, at least a surfactant and at least a hydrophilic polymer, and wherein, described phospholipid is at least a phosphatidylcholine; Described surfactant is at least a fat melting rhzomorph; Be selected from DSPE-mPEG-2000, DSPE-mPEG-5000 and composition thereof with described hydrophilic polymer, this method comprises freezing described preparation and stores at least three days.
8. the method for claim 7, it also comprises the described refrigerated Liposomal formulation of transportation and the described preparation that thaws in another position.
9. the method for claim 7, wherein, described phospholipid is at least a phosphatidylcholine; Described surfactant is at least a surfactant that is selected from single palmitoylphosphatidyl choline (MPPC), single lauroyl phosphatidylcholine (MLPC), single myristoyl phosphatidylcholine (MMPC), single stearoyl phosphatidylcholine (MSPC) and composition thereof; Be selected from DSPE-mPEG-2000, DSPE-mPEG-5000 and composition thereof with described hydrophilic polymer.
10. the method for claim 9, wherein, described phospholipid is dipalmitoyl phosphatidyl choline (DPPC); Described surfactant is single palmitoylphosphatidyl choline (MPPC); Be selected from DSPE-mPEG-2000, DSPE-mPEG-5000 and composition thereof with described hydrophilic polymer.
11. the method for claim 9, wherein, described phospholipid is dipalmitoyl phosphatidyl choline (DPPC); Described surfactant is single stearoyl phosphatidylcholine (MSPC); Be selected from DSPE-mPEG-2000, DSPE-mPEG-5000 and composition thereof with described hydrophilic polymer.
12. the method for claim 10, wherein, the mol ratio of DPPC: MPPC: DSPE-mPEG is about 90: 10: 4.
13. the method for claim 11, wherein, the mol ratio of DPPC: MSPC: DSPE-mPEG is about 90: 10: 4.
14. the process of claim 1 wherein that described nanoparticle formulations also comprises active agent, this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
15. the method for claim 14, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
16. the method for claim 15, wherein, described active agent is at least a antineoplastic agent.
17. the method for claim 16, wherein, described active agent is an amycin.
18. the method for claim 3, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
19. the method for claim 18, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
20. the method for claim 19, wherein, described active agent is at least a antineoplastic agent.
21. the method for claim 20, wherein, described active agent is an amycin.
22. the method for claim 4, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
23. the method for claim 22, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
24. the method for claim 23, wherein, described active agent is at least a antineoplastic agent.
25. the method for claim 24, wherein, described active agent is an amycin.
26. the method for claim 5, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
27. the method for claim 26, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
28. the method for claim 27, wherein, described active agent is at least a antineoplastic agent.
29. the method for claim 28, wherein, described active agent is an amycin.
30. the method for claim 6, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
31. the method for claim 30, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
32. the method for claim 31, wherein, described active agent is at least a antineoplastic agent.
33. the method for claim 32, wherein, described active agent is an amycin.
34. the method for claim 7, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
35. the method for claim 34, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
36. the method for claim 35, wherein, described active agent is at least a antineoplastic agent.
37. the method for claim 36, wherein, described active agent is an amycin.
38. the method for claim 9, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
39. the method for claim 38, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
40. the method for claim 39, wherein, described active agent is at least a antineoplastic agent.
41. the method for claim 40, wherein, described active agent is an amycin.
42. the method for claim 10, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
43. the method for claim 42, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
44. the method for claim 43, wherein, described active agent is at least a antineoplastic agent.
45. the method for claim 44, wherein, described active agent is an amycin.
46. the method for claim 11, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
47. the method for claim 46, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
48. the method for claim 47, wherein, described active agent is at least a antineoplastic agent.
49. the method for claim 48, wherein, described active agent is an amycin.
50. the method for claim 12, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
51. the method for claim 50, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
52. the method for claim 51, wherein, described active agent is at least a antineoplastic agent.
53. the method for claim 52, wherein, described active agent is an amycin.
54. the method for claim 13, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
55. the method for claim 54, wherein, described active agent is selected from anesthetics, antihistaminic, antineoplastic agent, antiulcerative, anti-outbreak medicine, muscle relaxant, immunosuppressant, anti-infective, NSAID (non-steroidal anti-inflammatory drug), photographic developer, nutrient and composition thereof.
56. the method for claim 55, wherein, described active agent is at least a antineoplastic agent.
57. the method for claim 56, wherein, described active agent is an amycin.
58. the method for claim 3, wherein, described hydrophilic polymer is by the key and the phospholipids incorporate of non-hydrolysis.
59. the method for claim 58, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
60. the process of claim 1 wherein that described freezing step is the part of freeze drying process.
61. the method for claim 60, wherein, described nanoparticle formulations also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
62. the method for claim 3, wherein, described freezing step is the part of freeze drying process.
63. the method for claim 62, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
64. the method for claim 4, wherein, described freezing step is the part of freeze drying process.
65. the method for claim 64, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
66. the method for claim 5, wherein, described freezing step is the part of freeze drying process.
67. the method for claim 66, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
68. the method for claim 7, wherein, described freezing step is the part of freeze drying process.
69. the method for claim 68, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
70. the method for claim 9, wherein, described freezing step is the part of freeze drying process.
71. the method for claim 70, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
72. the method for claim 10, wherein, described freezing step is the part of freeze drying process.
73. the method for claim 72, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
74. the method for claim 11, wherein, described freezing step is the part of freeze drying process.
75. the method for claim 74, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
76. the method for claim 12, wherein, described freezing step is the part of freeze drying process.
77. the method for claim 76, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
78. the method for claim 13, wherein, described freezing step is the part of freeze drying process.
79. the method for claim 78, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
80. the method for a storing nanoparticle formulations, this nanoparticle formulations have at least a amphiphile, at least a surfactant and at least a hydrophilic polymer, this method comprises to be made described preparation dehydration and stores at least three days time.
81. the method for claim 80, it also comprises the Liposomal formulation that transports described dehydration and at the described preparation of another position rehydration.
82. the method for claim 80, wherein, described nano-particle is a liposome.
83. the method for claim 82, wherein, described amphiphile comprises at least a phospholipid.
84. the method for claim 83, wherein:
A. described at least a phospholipid is selected from phosphatidylcholine, phosphatidyl glycerol, phosphatidylinositols, PHOSPHATIDYL ETHANOLAMINE, sphingomyelin and composition thereof;
B. described at least a surfactant is selected from LYSO-PHOSPHATIDYLCHOLINE LYSOPC that double-stranded phospholipid, fat melting rhzomorph, bile acid, myristoyl surfactant, palmityl surfactant, stearoyl surfactant, glycerin mono-fatty acid ester, ceramide, PEG-ceramide, C18-ether connects, polyethylene glycol-ethylene copolymer, block copolymer, fatty acid and composition thereof; With
C. described at least a hydrophilic polymer is selected from Polyethylene Glycol, polyaeryloyl morpholine, poly--the 2-ethyl-2-oxazoline, polyvinylpyrrolidone, methoxy poly (ethylene glycol) (mPEG) and composition thereof.
85. the method for claim 84, wherein, described hydrophilic polymer is by hydrolyzable key and phospholipids incorporate.
86. a method that stores Liposomal formulation, this Liposomal formulation have at least a phospholipid, at least a surfactant and at least a hydrophilic polymer, wherein, described phospholipid is at least a phosphatidylcholine; Described surfactant is at least a fat melting rhzomorph; Be selected from DSPE-mPEG-2000, DSPE-mPEG-5000 and composition thereof with described hydrophilic polymer, this method comprises to be made described preparation dehydration and stores at least three days.
87. the method for claim 86, it also comprises transportation described Liposomal formulation and at the described preparation of another position hydration.
88. the method for claim 87, wherein, described phospholipid is at least a phosphatidylcholine; Described surfactant is at least a surfactant that is selected from single palmitoylphosphatidyl choline (MPPC), single lauroyl phosphatidylcholine (MLPC), single myristoyl phosphatidylcholine (MMPC), single stearoyl phosphatidylcholine (MSPC) and composition thereof; Be selected from DSPE-mPEG-2000, DSPE-mPEG-5000 and composition thereof with described hydrophilic polymer.
89. the method for claim 88, wherein, described phospholipid is dipalmitoyl phosphatidyl choline (DPPC); Described surfactant is single palmitoylphosphatidyl choline (MPPC); Be selected from DSPE-mPEG-2000, DSPE-mPEG-5000 and composition thereof with described hydrophilic polymer.
90. the method for claim 88, wherein, described phospholipid is dipalmitoyl phosphatidyl choline (DPPC); Described surfactant is single stearoyl phosphatidylcholine (MSPC); Be selected from DSPE-mPEG-2000, DSPE-mPEG-5000 and composition thereof with described hydrophilic polymer.
91. the method for claim 89, wherein, the mol ratio of DPPC: MPPC: DSPE-mPEG is about 90: 10: 4.
92. the method for claim 90, wherein, the mol ratio of DPPC: MSPC: DSPE-mPEG is about 90: 10: 4.
93. the method for claim 80, wherein, described nanoparticle formulations also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
94. the method for claim 82, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
95. the method for claim 83, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
96. the method for claim 84, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
97. the method for claim 86, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
98. the method for claim 88, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
99. the method for claim 89, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
100. the method for claim 90, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
101. the method for claim 91, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
102. the method for claim 92, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
103. the method for claim 62, wherein, described hydrophilic polymer is by the key and the phospholipids incorporate of non-hydrolysis.
104. the method for claim 103, wherein, described Liposomal formulation also comprises active agent, and this active agent is selected from pharmacological activity reagent, flavouring agent, diagnostic reagent, nutrient, gene prod and composition thereof.
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| US60/710,156 | 2005-08-23 | ||
| PCT/US2006/032714 WO2007024826A2 (en) | 2005-08-23 | 2006-08-23 | Method of storing nanoparticle formulations |
Publications (2)
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| CN101282715A true CN101282715A (en) | 2008-10-08 |
| CN101282715B CN101282715B (en) | 2013-03-27 |
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| JP (1) | JP5227173B2 (en) |
| KR (2) | KR20120104438A (en) |
| CN (1) | CN101282715B (en) |
| AU (1) | AU2006283465B2 (en) |
| CA (1) | CA2620829C (en) |
| ES (1) | ES2587583T3 (en) |
| TW (1) | TWI388344B (en) |
| WO (1) | WO2007024826A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101668697B (en) * | 2007-03-30 | 2013-03-27 | 科技研究局 | An encapsulated quantum dot |
| CN106727329A (en) * | 2012-02-17 | 2017-05-31 | 效思因公司 | Temperature-sensitive nanoparticle formulations and preparation method thereof |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009059449A1 (en) * | 2007-11-05 | 2009-05-14 | Celsion Corporation | Novel thermosensitive liposomes containing therapeutic agents |
| US11679163B2 (en) | 2019-09-20 | 2023-06-20 | Hdt Bio Corp. | Compositions and methods for delivery of RNA |
| WO2021194672A1 (en) | 2020-03-23 | 2021-09-30 | Hdt Bio Corp. | Compositions and methods for delivery of rna |
| JP2024535351A (en) | 2021-09-22 | 2024-09-30 | エイチディーティー バイオ コーポレーション | Dry Nanoparticle Composition |
| JP2024535352A (en) | 2021-09-22 | 2024-09-30 | エイチディーティー バイオ コーポレーション | SARS-COV-2 RNA VACCINE COMPOSITIONS AND METHODS OF USE |
| JP2024535353A (en) | 2021-09-22 | 2024-09-30 | エイチディーティー バイオ コーポレーション | RNA vaccines against infectious diseases |
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| CA1256372A (en) * | 1985-04-11 | 1989-06-27 | Koichiro Miyazima | Process for producing liposome composition |
| KR900700079A (en) * | 1988-01-12 | 1990-08-11 | 후지하라 도미오 | Leak-proof liposome formulation |
| US5705187A (en) * | 1989-12-22 | 1998-01-06 | Imarx Pharmaceutical Corp. | Compositions of lipids and stabilizing materials |
| JPH06211645A (en) * | 1993-01-14 | 1994-08-02 | Mitsubishi Kasei Corp | Liposome freeze-dried preparation |
| JPH10511957A (en) * | 1995-01-05 | 1998-11-17 | ザ ボード オブ リージェンツ オブ ザ ユニヴァーシティ オブ ミシガン | Surface-modified nanoparticles and methods for their production and use |
| CA2227989A1 (en) * | 1995-08-01 | 1997-02-13 | Karen Ophelia Hamilton | Liposomal oligonucleotide compositions |
| GB9609779D0 (en) * | 1996-05-10 | 1996-07-17 | Univ Bruxelles | Freeze dried liposome encapsulated amphiphilic drug compositions and a process for the preparation thereof |
| US6143276A (en) * | 1997-03-21 | 2000-11-07 | Imarx Pharmaceutical Corp. | Methods for delivering bioactive agents to regions of elevated temperatures |
| US6726925B1 (en) * | 1998-06-18 | 2004-04-27 | Duke University | Temperature-sensitive liposomal formulation |
| US6200598B1 (en) * | 1998-06-18 | 2001-03-13 | Duke University | Temperature-sensitive liposomal formulation |
| JP2003504389A (en) * | 1999-07-16 | 2003-02-04 | アルザ・コーポレーション | Liposome composition resistant to freeze / thaw damage |
| AR036316A1 (en) * | 2002-08-29 | 2004-08-25 | Monte Verde S A | A PHARMACEUTICAL COMPOSITION OF SMALL SIZE LIPOSOMES AND PREPARATION METHOD |
| JP4293586B2 (en) * | 2002-08-30 | 2009-07-08 | 浜松ホトニクス株式会社 | Nanoparticle production method and production apparatus |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101668697B (en) * | 2007-03-30 | 2013-03-27 | 科技研究局 | An encapsulated quantum dot |
| CN106727329A (en) * | 2012-02-17 | 2017-05-31 | 效思因公司 | Temperature-sensitive nanoparticle formulations and preparation method thereof |
| CN106727329B (en) * | 2012-02-17 | 2020-11-03 | 效思因公司 | Thermosensitive nanoparticle preparation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200803918A (en) | 2008-01-16 |
| HK1120731A1 (en) | 2009-04-09 |
| CN101282715B (en) | 2013-03-27 |
| WO2007024826A3 (en) | 2007-10-11 |
| ES2587583T3 (en) | 2016-10-25 |
| CA2620829A1 (en) | 2007-03-01 |
| WO2007024826A2 (en) | 2007-03-01 |
| AU2006283465B2 (en) | 2011-11-03 |
| TWI388344B (en) | 2013-03-11 |
| KR20120104438A (en) | 2012-09-20 |
| JP5227173B2 (en) | 2013-07-03 |
| KR20080046672A (en) | 2008-05-27 |
| AU2006283465A1 (en) | 2007-03-01 |
| EP1937214B1 (en) | 2016-07-27 |
| CA2620829C (en) | 2013-10-29 |
| KR101209496B1 (en) | 2012-12-07 |
| JP2009506038A (en) | 2009-02-12 |
| EP1937214A2 (en) | 2008-07-02 |
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